Regulators of G-protein signaling (RGS) accelerate guanosine triphosphate (GTP) hydrolysis by G.sub.i, but not by G.sub.s class .alpha.-subunits (Popov et al. (1997) Proc. Nati. Acad. Sci. USA 94:7216-20). RGS proteins were first identified in genetic screens in fungi and nematodes as negative regulators of G-protein signaling (Dolhman et al. (1995) Mol. Cell. Biol. 15:3635-43). RGS proteins have been shown to function as GTPase-activating proteins. It has additionally been proposed that RGS proteins may act as effector antagonists by occluding the effector-binding sites on G-protein .alpha.-subunits (Helper et al. (1997) Proc. Natl. Acad. Sci. USA 94:428-432).
RGS has been implicated in a distinct molecular mechanism with the potential to modulate G-protein responses. Proteins containing the RGS domain can directly control aspects of G-protein stimulated signaling pathways. RGS proteins appear to enhance the endogenous GTPase activity of G-proteins, thus decreasing the half-life of the active GTP-bound state and limiting the duration of G.alpha..sub.i signaling.
The glucose-dependent insulinotropic peptide receptor (GIP-R) is a member of the G-protein coupled receptors. GIP was first isolated from porcine small intestine and was described as a member of the secretin family of gastrointestinal regulatory peptides (Tseng and Zhang (1998) Endocrin. 139:4470-75). In the presence of glucose, GIP is a potent stimulator of insulin release by pancreatic islet .beta.-cells. GIP may represent an important hormonal mediator in the entero-insular axis. Insulinotropic properties of GIP in diabetic patients have been shown to be diminished despite elevated serum levels of GIP. While the precise mechanism for the decline in insulinotropic activity of GIP in diabetic patients has not been defined, agonist-induced desensitization of G-protein-coupled receptors is well documented (Premont et al. (1995) FASEB J 9:175-182).
Recently, an interaction of the G-protein with members of RGS proteins has been demonstrated to mediate a desensitization mechanism. RGS proteins act as GTPase activating proteins to decrease the half-life of the activated G .alpha.-subunit (Koelle et al. (1996) Cell 84:115-125; Druey et al. (1996) Nature 379:742-46).
Additionally, RGS proteins may be involved in cell migration. Cell migration is a required behavior in the development and maintenance of multicellular organisms. Generally, cells migrate in response to various chemoattractants and chemorepellents in the environment (Bowman et al. (1998) J. Biol. Chem. 273:28040-48). Chemoattractants provide a directional signal to cells leading to migration of the cells towards the source of the chemoattractant (Butcher et al. (1996) Science 272:60-66; Mackay, C. R. (1996) J. Exp. Med. 184:799-802). Chemoattractants also direct the rapid, integrin-dependent adhesion of leukocytes to various cell-associated or extracellular proteins if the corresponding chemoattractant receptor is expressed at high levels. RGS proteins appear to be involved as most leukocyte chemoattractants mediate their activity by binding and stimulating specific G.alpha..sub.i -oupled receptors.
RGS proteins constitute a family of proteins characterized by an RGS domain. A number of RGS proteins have been identified and several have been shown to function as GTPase-activating proteins (Chatterjce et al. (1997) Genomics 45:429-33). Identification of other members of the RGS family are needed.
Because of the complexity of the immune response and regulation of heterotrimeric G-protein signaling, additional mechanisms are needed to modulate such functions. Additionally, methods are needed to regulate an immune response, and provide therapies for a range of diseases.